Isoindolobenzimidazolones



United States Patent 3,329,684 ISOINDOLOBENZIMIDAZOLONES William J. Houlihan, Mountain Lakes, NJ., assignor to Sandoz Inc., Hanover, NJ.

No Drawing. Filed July 1, 1964, Ser. No. 379,749 10 Claims. (Cl. 260-3091) ABSTRACT OF THE DISCLOSURE This invention provides three classes of compounds which are generically represented by the formula lie wherein R is either lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl; or

each of R R R R and R is, independently, either a hydrogen atom (-H); lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl; lower alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy and butoxy; primary amino (NH a chlorine atom (Cl); a bromine atom (Br); a fluorine atom (F); or trifluoromethyl (-CF with the proviso that a plurality of trifluoromethyl groups are not ortho to each other;

each of R and R is, independently, either a hydrogen atom (H); a fluorine atom (F); a chlorine atom (Cl); -SR OR lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl; and trifluoromethyl (CF with the proviso that both R and R are not trifl'uoromethyl in the same compound;

R is lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl; and

B is=NI-I for the first class of compounds;

is=0 for the second class of compounds; and is=S for the third class of compounds.

The compounds -of this invention are prepared by admixing and heating an o-acylbenzoic acid (II) with an o- (HB)substituted aniline (III) in an inert solvent with an acid catalyst according to the'reaction scheme:

wherein each of R, R R R R and B has its aboveascribed meaning, as it does throughout the entire disclosure.

The inert solvent is one which is inert, at the reaction temperature, with both the reactants and the reaction product. Suitable solvents are polar solvents, e.g. dimethylformamide, diethylformamide, dioxane, chlorobenzene and pyridine; benzenes, e.g. benzene, toluene, dichlorobenzene; cycloalkanes, e.g. cyclohexane; and other highboiling hydrocarbons, e.g. .tetralin.

The temperature at which the reaction is eifected is any temperature from room temperature (20 C.) to the boiling point of the selected solvent system.

The acid catalyst is either an organic acid or an inorganic acid. Para-toluenesulfonic acid is preferred, but other acids, such as alkane sulfonic, e.g. methane sulfonic; arylsulfonic, e.g. phenylsulfonic; phosphoric; acid ion exchange resin, e.g. Dowex50; and acid activated aluminosilicates, e.g. Tonsil, also produce favorable results.

Compounds of this invention are stable compounds useful as sedatives, tranquilizers and antidepressants. They are administered either orally or parenterally in daily doses from two hundred milligrams to four hundred milligrams. Compounds of this invention are CNS (central nervous system) active and antagonize amphetamines CNS activity.

The examples are merely illustrative of the invention. Any contemplated combination of substitution within the scope of Formula I is obtained in the same manner as hereinafter set forth by the corresponding selection of reactants. Corresponding compounds of the first, second and third classes of compounds are prepared in the same manner with only an appropriate change in reactant III.

In said examples, unless otherwise specified, all parts are parts by weight, all temperatures are in degrees centigrade, and the relationship between parts by Weight and parts by volume is the same at that between the kilogram and the liter.

EXAMPLE 1 4a-phenyl-is0indolo-5H- [1,2-b] benzz'midazol-II-one Admix in a flask equipped with a stirrer and a Dean- Stark tube (for removing Water) 22.6 parts (0.10 mole) of o-benzoylbenzoic acid, 16.2 parts (0.15 mole) of ophenylenediamine, 0.2 part of p-toluene sulfonic acid and 350 parts by volume of toluene. Stir and reflux the obtained mixture until water ceases to separate in the Dean-Stark tube. Remove the solvent in vacuo in a rotary evaporator. Add the oily residue to methanol to obtain 3 4 t light yellow solid. Recrystallize from ethanol-Water a rotary evaporator. Recrystallize from methanol to o obtain 19.6 parts of the title compound, melting obtain 3.3 parts of title compound, M.P. 233 to 235. point (M.P.) 158. By replacing the o-acetylbenzoic acid (H) and the 4- In this example o-benzoylbenzoic acid is used as the chloro-o-phenylene diamine (III) by their counterparts Compound II and oaphenylenediamine, as the Compound 5 defined by substituents in the following table, com- III. The example is repeated to obtain corresponding parable results and corresponding compounds are ob- :ompounds with comparable results replacing said Comtamedpounds II and III as follows:

R i R R R R B R o=0 HE -R'' a a: a a e a 8 6 R5 HZN (c) Pr O Me iPr -H -o1 NH l (d) iPr Me O-Et S-Me H. 0 7 0H (e) -Bu -o1u Et CF SEt s (II) (III) 1 R R4 Ra Ra R7 B (a) -H -11 SiPr O-Bu NH (b) -CH; H -11 O-iPr -H s (l)-Bu (c) -11 Cl H OBu NH I (1 Q -Pr H OMe O-Et 0 (e) F -11 iPr Et CF s 1 r Me OiPr Me Pr NH 01 (g)- O-Me -H Et iPr -H 0 )Et 11 OF3 -11 H -o1 Bu s I (i) Q-Nm OPr -11 F F 0 JFa Where Me is methyl, Et is ethyl, Pr is propyl, iPr is isopropyl, and Bu is butyl.

EXAMPLE 2 EXAMPLE 3 4 a-methyl-8-ch loro-isoindolo-S H- [1 ,2-b] benzimidazol- 4a -phenyl-8-chl0ra-isoindolo-SH- [1,2-b benzimidazol- 1-1-one 11-0ne N-- -Cl Y /NH\ 0 Admix in a flask equipped with a stirrer and a Dean- N -01 Stark tube (for removing water) 8.2 parts (0.05 mole) Y of o-acetylbenzoic acid, 143- parts (0.10 mole) of 4- O chlolophenyle'ne diamine, 250 Parts by Volume of Xylene Admix in a flask equipped with a stirrer and a Dean- 'and .03 part of p-toluenesulfonic acid. Stir and reflux Stark tube 113 parts (0.05 mole) of o-benzoylbenzoic the obtained mixture until water ceases to separate in acid, 10.0 parts (0.07 mole) of 4-chloro-o-phenylenedithe Dean-Stark tube. Remove the solvent in vacuo in amine, 0.5 part of p-toluenesulfonic acid and 250 parts by volume of toluene. Stir and reflux the obtained mixture until water ceases to separate in the Dean-Stark tube. Remove the solvent in vacuo in a rotary evaporator. Add the oily residue to methanol to obtain a light yellow solid. Recrystallize from DMF-methanol-water to obtain 5.3 parts of the title compound, M.P. 210 to 211.

EXAMPLE 4 4a- (p-tolyl) -8-chlor0-isoind0l0-5H- [1,2-b] benzimidazol- Admix in a flask equipped with a stirrer and a Dean- Stark tube 12.0 parts (0.05 mole) of o-(p-tolyl)-benzoic acid, 10.0 parts (0.07 mole) of 4-chloro-o-phenylene diamine, 0.5 part of p-toluene-sulfonic acid and 250 parts by volume of toluene. Stir and reflux the obtained mixture until water ceases to separate in the Dean-Stark tube. Remove the solvent in vacuo in a rotary evaporator. Add the oily residue to methanol to obtain a light yellow solid. Recrystallize from DMF-methanol-water to obtain 9.1

parts of the title compound, M.P. 210 to 212.

EXAMPLE 5 4a-(pwhlorophenyl)-8-chloro-isoindolo-5H-[1,2-b1benzim'idazdl-ll-one 6 EXAMPLE 6 4a-phenyl-8-meth0xy-is0indolo-5H- [1,2-bl benzimidazol- 11-0ne Admix in a flask equipped with a stirrer and a Dean- Stark tube 3.5 parts (0.015 mole) of o-benzoylbenzoic acid, 3.0 parts (0.022 mole) of 4-methoxy-o-phenylenediamine, 0.2 part of p-toluenesulfonic acid and 75 parts by volume of toluene; Stir and reflux the obtained mixture until water ceases to separate in the Dean-Stark tube. Remove the solvent in vacuo in a rotary evaporator. Add the oily residue to methanol to obtain alight yellow solid. Recrystallize from DMF-water to obtain 4.7 parts of the title compound, M.P. 108 to 111.

EXAMPLE 7 4a-methyl-isoindolo-5H-[1,2-17]benzimidazol-lI-ane NH W Admix in a flask equipped with a stirrer and a Dean- Stark tube 4.1 parts (0.025 mole) of o-acetylbenzoic acid, 5.4 parts (0.050 mole) of o-phenylene diamine, parts by'volume of toluene and 0.1 part of p-toluene sulfonic acid. Stir and reflux the obtained mixture until Water ceases to separate in the Dean-Stark tube. Remove the solvent in vacuo in a rotary evaporator. Add the oily residue to methanol to obtain a light yellow solid. Recrysjtallize from i-propanol to obtain 3.1 parts of the title compound, M.P. 183 to 184.

EXAMPLE 8 4a- (p-chlorophenyl) -8-methoxy-isoind0lo- 5H- [1,2-b] benzimidazol-II-one t QTH I f) I OCH Admix in a flask equipped with a stirrer and a Dean- Stark tube 6.8 parts (0.026 mole) of o (-p-chlorobenzoyl)- benzoic acid, 5.0 parts (0.036 mole) of 4-methoxy-ophenylene diamine, 150 parts by volume of toluene and 0.3 part of p-toluenesulfonic acid. Stir and reflux the obtained mixture until water ceases to separate in the Dean- Stark tube, Remove the solvent in vacuo in a rotary evaporator. Add the oily residue to methanol to obtain a light yellow solid. Recrystallize from DMF-water to obtain 8.2 parts of the title compound, M.P. 112

EXAMPLE 9 4a-phenyl-isoind0la[1 ,Z-blbenzoxazol-I 1-0ne Admix in a flask equipped with a stirrer and a Dean- Stark tube 11.3 parts (0.05 mole) of o-benzoylbenzoic acid, 8.2 parts (0.075 mole) of o-aminophenol, 0.2 part of p-toluenesulfonic acid and 150 parts by volume of toluene.

methanol-water to obtain 8.6 parts of the title compound,

M.P. 125 to 128.

EXAMPLE l0 4a-phenyl-is0ind0l0[1,Z-b] benzothiazol-I] -0ne Admix in a flask equipped with a stirrer and a Dean- Stark tube 11.3 parts (0.05 mole) of o-benzoylbenzoic mixture until water ceases to separate in the Dean-Stark tu'be. Remove the solvent in vacuo in a rotary evaporator. Add the oily residue to methanol to obtain a light yellow solid. Recrystallize from chloroform-ether to obtain 11.1

parts of the title compound, M.P. 144 to 148".

It is thought that the invention will be understood from the foregoing description and it is apparent that various changes may be made In the products without departing from the spirit and scope of the invention or sacrificing its material advantages, the compounds invention.

What is claimed is: 1. A compound of the formula hereinbetore described being merely illustrative of embodiments of the wherein R- is lower alkyl; each of R and R is a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, primary amino, a chlorine atom, a bromine atom, a fluorine atom and trifluoromethyl, with the proviso that at most one of R and R is trifluorornethyl; and each of R and R is a member selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, lower alkylthio, lower alkoxy, lower alkyl and trifluoromethyl, with the proviso that at most one of R and R' is trifluoromethyl. 2. 4a-methyl-8-chloro-isoindolo-5H [1,2-b1benzimidazol-l l-one.

3. 4a-methyl-isoindolo-5H-[1,2-b1benzimidazol-1l-one. 4. A compound of the formula wherein R is 3-R -4-R -5-R -phenyl; each of R R R R and R is a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, primary amino, a chlorine atom, a bromine atom, a fluorine atom and trifluoromethyl, with the proviso that a plurality of trifluoromethyl groups are not ortho to each other; and each of R and R is a member selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, lower *alkylthio, lower alkoxy, lower alkyl and trifluoromethyl, with the proviso that at most one of R and R is trifluoromethyl. 5. 4a-phenyl-isoindolo-5H-[ l,2-b]benzimidaZol-l l-one. 6. 4a-phenyl-8-chloro-isoindolo-SH [l,2-b]benzimidazol-l l-one.

7. 4a-(p-tolyl)-8-chloro-isoindolo-5H [1,2-blbenzi-midazol-l l-one.

8. 4a-(pchlorophenyl)-8chloro-isoindolo-5H [1,2-b] benzimidazol-l l-one. 9. 4a-phenyl-8-methoxy-isoindolo-5H [1,2-b1benzimidazol-l l-one.

10. 4a-(p-chloropheny1)-8-methoxy-isoindolo-5H 2-b]benzimidazol-11-one.

No references cited.

ALEX MAZEL, Primary Examiner. RICHARD J. GALLAGHER, Assistant Examiner. 

